The present invention relates to the discovery that phytoestrogen compounds are useful for up-regulating choline acetyltransferase mRNA and nerve growth factor mRNA in the brain, and therefore are useful for inhibiting the development of Alzheimer's disease and related dementias.
Alzheimer's disease and related dementias cause marked loss in cognitive function, often reducing an afflicted person to an invalid state. No cure is known for Alzheimer's and related dementias, and the causes of these diseases are not well understood.
Alzheimer's disease, however, is strongly associated with decreased choline acetyltransferase activity and the loss of cholinergic neurons. Neurochemical Studies of Early-Onset Alzheimer's Disease: Possible Influence on Treatment, Francis et al., Lancet, Vol. 4, pp. 7-11 (1985); Alzheimer's Disease: A Cell Biological Perspective, Kosik, Science, Vol. 256, pp. 780-83 (1992), both incorporated herein by reference. Cholinergic neurons appear to be essential for learning and memory processes, and choline acetyltransferase (hereinafter "ChAT") activity and nerve growth factor (hereinafter "NGF") are important for the function of cholinergic neurons. Ovarian Steroid Deprivation Results in a Reversible Learning Impairment and Compromised Cholinergic Function in Female Sprague-Dawley Rats, Singh et al., Brain Research, Vol. 644, pp. 305-12 (1994); Effects of Estrogen Replacement on the Relative Levels of Choline Acetyltransferase, trkA, and Nerve Growth Factor Messenger RNAs in the Basal Forebrain and Hippocampal Formation of Adult Rats, Gibbs et al., Experimental Neurol., Vol. 129, pp. 70-80 (1994), both incorporated herein by reference.
Postmenopausal estrogen treatment has been shown to reduce the incidence of Alzheimer's disease and related dementias, to relieve symptoms of Alzheimer's disease, and to preserve cognitive function in women. Estrogenic Effects on Memory in Women, Sherwin, B., Ann. N.Y. Acad. Sci., 743, pp. 213-31 (1994); Oestrogen Replacement Therapy and Alzheimer's Disease, Paganini-Hill, A., Brit. J. Obstet. & Gynaecol., 103, pp. 80-86 (1996), both incorporated herein by reference. One mechanism by which supplemental estrogen may provide these beneficial effects is by increasing ChAT, ChAT activity, and NGF messenger RNA. Gibbs et al., Experimental Neurol. (above), Singh et al., Brain Research (above), and Overiectomy Reduces ChAT Activity and NGF mRNA Levels in the Frontal Cortex and Hippocampus of the Female Sprague-Dawley Rat, Singh et al., Abstr. Soc. Neurosci., Vol. 19, p. 1254 (1993), incorporated herein by reference. Unfortunately, commonly used estrogens can significantly increase the risk of breast and uterine cancers in women, and have intolerable side effects for men and some women.
It is desirable, therefore, to find compounds like estrogen which can maintain normal levels of ChAT and NGF in cholinergic neurons in basal forebrain (such as septum) and their target brain tissues (cerebral cortex and hippocampus) to reduce or prevent loss of cholinergic neurons to prevent or delay the onset on Alzheimer's disease and related dementias, or to relieve the symptoms of Alzheimer's disease and related dementias.
Phytoestrogens are compounds that are structurally similar to estrogens which are derived from plants such as legumes, clovers, kudzu root (pueraria lobata), and oilseeds such as rapeseed. Phytoestrogens--particularly the isoflavones derived from soy and clover such as genistein, daidzein, glycitein, and their glucosidic derivatives--exhibit estrogenic properties in some mammalian and human tissues, and exhibit anti-estrogenic properties in other tissues by competitively inhibiting estrogen binding at estrogen receptor sites. Certain phytoestrogens, particularly genistein, are also known to have tyrosine kinase inhibitory activity. Unlike estrogen, however, these isoflavone phytoestrogens are not associated with an increased risk of cancer, and may actually inhibit the development of breast and uterine cancers.